HIV protease inhibitors are beneficial to HIV patients, however, lipodystrophy, hyperlipidemia, and diabetes are among the significant clinical problems associated with their use. Human and animal studies indicate that insulin resistance is a key factor in the development of these metabolic sequelae, but the etiology is unknown. An endogenous protease that is known to be involved in insulin action that is also affected by the protease inhibitors would be a likely target candidate. Insulin-degrading enzyme (also called insulysin) is such a protein. Insulin-degrading enzyme is involved in mediating insulin action on protein degradation and peroxisomal fatty acid oxidation. The objective of the studies proposed here is to determine which HIV protease inhibitors inhibit insulin degradation by insulin-degrading enzyme, and how that inhibition affects protein and lipid metabolism. It is hypothesized that HIV protease 1 inhibitors induce insulin resistance and alter protein and lipid metabolism by inhibiting the action of insulin-degrading enzyme. The following four Specific Aims will address this hypothesis: 1) Identify HIV protease inhibitors that inhibit insulin-degrading enzyme in vitro and in cells; 2) Evaluate the capacity of HIV protease inhibitors to alter insulin pharmacokinetics in vivo\ 3) Determine the extent to which HIV protease inhibitors alter the inhibition of protein metabolism by insulin; and 4) Determine the extent to which HIV protease inhibitors alter insulin- induced changes in lipid metabolism. Enzyme preparations will be used to characterize the effect of HIV protease inhibitors on insulin-degrading enzyme and its function. Cell culture will be used to demonstrate these actions in whole cell, and their consequences on insulin action. Animals will be treated with HIV protease inhibitors to extend these studies and verify they are physiologically relevant. Understanding how protease inhibitors cause insulin resistance is key to helping HIV/AIDS patients. If insulin-degrading enzyme is involved, HIV protease inhibitors could be developed or screened for minimal reactivity with IDE.